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Cryo-EM and MD modeling reveal the mechanism by which the potent neurotoxin α-latrotoxin forms calcium-permeable membrane pores. The black widow spider is one of the scariest spider species.
Cryo-EM and MD modeling reveal the mechanism by which the potent neurotoxin α-latrotoxin forms calcium-permeable membrane pores. The black widow spider is one of the scariest spider species. Its venom is a cocktail of seven different toxins that attack the nervous system. These so-called latrotoxins specifically paralyze insects and crustaceans. However, one of these toxins, α-latrotoxin, targets vertebrates and is toxic to humans. It disrupts the transmission of nerve signals, causing harmful effects.
As soon as α-latrotoxin binds to specific receptors of synapses (contacts between nerve cells or between nerve cells and muscles), calcium ions enter the presynaptic membranes of signaling cells in an uncontrolled manner. This causes neurotransmitters to be released, causing strong muscle contractions and spasms.
Despite the apparent simplicity of this process, there is a very complex mechanism behind it. Scientists from the University of Münster (Germany) deciphered the structure of α-latrotoxin before and after membrane insertion with near-atomic resolution.
To better understand the mechanism of calcium entry into the presynaptic membrane, experts from the Center for Soft Nanoscience at the University of Münster (Prof. -EM) and computer modeling of molecular dynamics (MD).
They showed that the toxin undergoes a surprising transformation when it binds to the receptor. Part of the toxic molecule forms a radical that penetrates the cell membrane like a syringe. Specifically, this stalk forms a small pore in the membrane that acts as a calcium channel. MD simulations showed that calcium ions can enter the cell through a selective gate located just above the pore.
With these results, researchers now better understand how α-latrotoxin works. Christos Gatsogiannis explains: “The toxin mimics in a very complex way the function of calcium channels in the presynaptic membrane.” “It is therefore different in every respect from all previously known toxins.” New discoveries open up a wide range of potential applications; Latrotoxins have significant biotechnological potential, including the development of improved antidotes, stroke treatments, and new biopesticides.
The results of the research were recently published in the journal Nature Communication. In previous work, the research team led by Christos Gatsogiannis had already solved the structure of insect-specific latrotoxins in black widow spider venom before they were inserted into the membrane.
Source: Port Altele
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